The invention relates to a process for the synthesis of Cefuroxime acid (I), i.e. (6R, 7R)-7-[[2-furanyl (sin-methoxyimino)acetyl]amino]-3-carbamoyloxymethylceph-3-em-4-carboxylic) acid, and the salts thereof, starting from 3-hydroxymethylceph-3-em precursors with activated isocyanates in carbonic acid esters.
Cefuroxime is a cephalosporin widely used in the treatment of bacterial infections thanks to its effective, broad spectrum antibacterial activity against gram-negative bacterials, in particular in the treatment of immunodepressed patients. 
The acid product is the precursor both of the corresponding sodium salt, for the injection administration, and of the corresponding 1-acetyloxy ester (Cefuroxime axetil), for the oral administration.
Said molecules are valuable in that they are highly resistant to xcex2-lactamases due to the methoxyimino group present in the side chain at the 7- position of the cephalosporanic ring.
As far as the carbamoylation step of the 3-hydroxymethylceph-3-em precursors is concerned, the known synthetic routes for the preparation of Cefuroxime make use of solvents, which involves potential risks connected with their inflammability and toxicity. The method disclosed in U.S. Pat. No. 3,966,717 comprises the conversion of diphenylmethyl-3-hydroxymethyl-7xcex2-(thien-2-yl) acetamidoceph-3-em-4-carboxylate into the corresponding 3-carbamoyloxymethyl derivative by reaction with trichloroacetylisocyanate in acetone and subsequent hydrolysis.
On the other hand, the synthesis disclosed in U.S. Pat. No. 4,284,767 comprises the reaction of (6R,7R)-7-[[2-furanyl (sin-methoxyimino)acetyl]amino]-3-hydroxymethylceph-3-em-4-carboxylic acid with dichlorophosphinylisocyanate in tetrahydrofuran and the subsequent recovery of the product in the form of the sodium salt.
Finally the synthesis described in U.S. Pat. No. 4,775,750 comprises the conversion of the same intermediate by reaction in methyl or ethyl acetate with chlorosulfonyl isocyanate.
It has now surprisingly been found that Cefuroxime 3-hydroxymethyl precursors can be carbamoylated by reaction with activated isocyanates, using carbonic acid C1-C4 esters, preferably dimethylcarbonate and diethylcarbonate, as reaction solvents. The risks involved by the use of said solvents are remarkably lower than those connected with the use of the solvents cited above. Furthermore, said alkyl carbonates have remarkably lower toxicity than the solvents reported above, THF, alkyl acetates and acetone.
It should be pointed out that said reaction with isocyanates, which are extremely aggressive reactants, in solvents such as alkyl carbonates, has never before been reported in literature.
In the following table, the various solvents cited above are compared. The reported data are those of the respective safety requirements reported on MSDS (Material Safety Data Sheet)xe2x80x94OHS.
It is clear that the use of carbonic acid esters, in particular dimethyl or diethyl carbonate, involves much lower potential risks than those expected when using the solvents cited in the prior art patents.
The present invention provides remarkable advantages in the industrial processes for the production of Cefuroxime.
In fact, the method of the invention provides good quality Cefuroxime acid in yields quite comparable with those expected with the prior art methods.
Moreover, the acid product can easily be converted into the corresponding pharmaceutically acceptable salt or ester, preferably into Cefuroxime sodium salt and Cefuroxime axetil, by using conventional techniques known to those skilled in the art.
The process of the present invention comprises the conversion of a Cefuroxime 3-hydroxymethyl or 3-hydroxymethyl-ceph-3-em precursor into the corresponding 3-carbamoyloxymethyl derivative by reaction in a solution of the precursor at a concentration ranging from 1 to 20% by weight, with an activated isocyanate/precursor molar ratio ranging from 1 to 5, wherein the activated isocyanate is preferably chlorosulfonyl isocyanate, using as solvent a carbonic acid C1-C4 alkyl ester, preferably dimethylcarbonate, at temperatures from xe2x88x9240 to 20xc2x0 C., preferably from 0 to 10xc2x0 C.
The progress of the carbamoylation reaction is monitored by HPLC chromatography. The reaction is over in 15÷60 minutes, when the substrate content in the final mixture decreases below 2% of the starting amount.
The reaction is then quenched by addition of water or, preferably, of an acidic aqueous solution, preferably an aqueous hydrochloric acid solution.
The product can be optionally filtered or, alternatively, recovered as the sodium salt as described in U.S. Pat. No. 4,775,750.
The following examples illustrate the process of the invention in greater detail.